40 International Journal of Modern Anthropology Int. J. Mod. Anthrop.(2012) 5 : 40-58 Available online at: www.ata.org.tn ; doi: http://dx.doi.org/10.4314/ijma.v1i5.3 Review Synthetic Report Origins and spreads of Alpha 1 antitrypsin variants in world human populations: a synthetic review Sabri Denden¹, ², Jemni Ben Chibani², Amel Haj Khelil², ³ Sabri Denden obtained his Ph.D. in Biological sciences and Biotechnology from the High Institute of Biotechnology of Monastir, University of Monastir. Responsible of the teaching of undergraduate courses of Genetics and Molecular Biology in the Higher School for Health Sciences and Techniques of Tunis. Author and coauthor of many studies in Human Genetics particularly in the subject of alpha 1 antitrypsin deficiency. E. mail: [email protected] - ¹The higher school for health Sciences and techniques of Tunis, Tunisia; ²Biochemistry and Molecular Biology Laboratory, Faculty of Pharmacy of Monastir,University of Monastir, Tunisia; ³ High Institute of Biotechnology of Monastir, University of Monastir, Tunisia Abstract - Human Alpha 1 antitrypsin (AAT) or protease inhibitor (PI) is a highly polymorphic glycoprotein. In this review report distributions of all detected AAT allelic variants in different world populations are collected showing their anthropological usefulness. Some variants are related to AAT deficiency (AATD) which is one of the most common genetic disorders worldwide. Data on PIS and PIZ, most common AATD mutations, and their worldwide distribution are also reported. Studies on DNA haplotypes were particularly useful for the estimations of PIS and PIZ mutations ages and worldwide spread. According to these data, it seems very likely that the PIZ mutation occurred in Sweden and was spread into the rest of the European continent via the Baltic countries. However, in a second hypothesis authors suggested multiple origins of this mutation. The highest frequencies of the PIS mutation in the Iberian Peninsula were linked to an early occurrence of the mutation in this region, before its spread throughout the Europeans countries and the Iberian Peninsula settlements and trading networks. However, the PIS allele may have been further dispersed by multiple occurrences of the mutation. This multiple origins of AAT variants could explain the higher frequencies and haplotype diversities in PIM1Val and PIM2 alleles, rather than their older base alleles (PIM1Ala and PIM3, respectively). Data on rare variants, which seem not to be so rare in some populations, are still lacking. The only reliable data, on the age of a rare AATD variant, was given on an autochthonous allele (NullOurém). Key words: Alpha 1 antitrypsin, allelic variants, worldwide distribution, origins and spread of mutations. 41 International Journal of Modern Anthropology (2012) Introduction The alpha1-antitrypsin (AAT), the most important general protease inhibitor (PI), is a highly polymorphic glycoprotein with more than 120 allelic variants belonging to a genetic system firstly designated “system PI”. These variants are generally classified alphabetically by the PI nomenclature, in terms of their electrophoretic mobility (Fagerhol and Laurell, 1970): for example the PIB variant is the most anodal, PIM the middle and most common one, and PIZ the most cathodal. Some of these allelic variants are associated with deficiency in AAT. This alpha 1 antitrypsin deficiency (AATD) represents a common hereditary disorder that mainly manifests as obstructive lung diseases and less common liver diseases. The AAT is a 52 kDa molecule synthesized mainly by hepatocytes. This is the main serine-protease inhibitor in the plasma, with normal circulating concentrations showing intra and inter- populations variation in a range from 0.9 to 3.5 g/L. The AAT is an acute phase protein, characterized by a rapid increase in its synthesis during the acute phase of inflammation, to address the imbalance of the protease-antiprotease balance, caused by increased proteolytic activity at the inflammation site (Jeppsson and Franzen, 1982). Despite the dissemination of AAT in all organs of the body, its main function is to be exercised in lung parenchyma, where it serves to protect the fragile alveolar tissue destruction by neutrophil elastase (NE), a powerful protease that destroy the major structural proteins of the cells. Mutations in the PI gene (also called SERPINA1), which encodes the AAT, are the cause of abnormal synthesis and secretion of AAT. Several AAT mutations are simple polymorphisms that not affect neither the amount of protein in serum nor its function (M variants: M1 (Ala213Val GCG→GTG), M2 (Arg101His CGT→CAT) and M3 (Glu376Asp GAA→GAC) are the most common normal variants). Some variants (I (Arg39Cys CGC→TGC), S (Glu264Val GAA→GTA), P (Val256Asp GAT→GTT)) are accompanied by a slight decrease in protein concentration (60 to 70% of normal rate). Other variants (Z (Glu342Lys GAG→AAG), Mmalton (ΔPhe52 delTTC) are accompanied by a dramatic decrease of AAT (less than 20% of normal rate) or its total disappearance (the null variants as Nullbellingham (Lys217AAG →StopTAG) (Crystal et al., 1990). PIS and PIZ AATD alleles are the most commonly encountered while other variants are rarely reported (Luisetti and Seersholm, 2004). 42 Anthropological history of Alpha 1 antitrypsin variants / Denden et al. Alpha 1 antitrypsin gene evolution The serpins (Serine Protease Inhibitors) family regroups more than 700 constituents. Several data, related to the serpin genes evolution and variations in mammals between humans and higher primates, exist. The PI gene is located on chromosome 14q32.1, within the serine protease inhibitor cluster. This region, spanning approximately 320 kb, also includes α1-antitrypsin pseudogene sequence (PIL), α1- antichymotrypsin (ACT), corticosteroidbinding globulin (CBG), protein C inhibitor (PCI) and kallistatin (PI4) Genes. The similarities of the exon-intron structures between the AAT and alpha 1 antichymotrypsin and their proximity to the 14q31 position indicates the recent divergence of these genes (about 100 to 250 million years ago) (Bao et al., 1987). The sequencing of coding exons (exons II to V) of the AAT in the chimpanzee and the gorilla has shown that there is one difference in one amino acid from human AAT M1 (Ala213) (a difference between the protein in position 385: Methionine in human, Valine in the chimpanzee) (Nukiwa et al., 1996). Since the base alleles of most mutation were clearly established and according to parsimony principle, it becomes possible to establish a phylogenetic tree of the AAT variants (Figure1).The PIM1 allele (Ala213) is the initial allele, all other derived by one or more substitutions. Within this tree, the PIM4 allele could have been arisen either on PIM1 (Val213) or on PIM2 alleles or from intragenic recombination between both. 43 International Journal of Modern Anthropology (2012) Figure 1. Phylogenetic tree of the AAT variants based on the parsimony principle, modified from Nukiwa et al., 1996. 44 Anthropological history of Alpha 1 antitrypsin variants / Denden et al. AAT gene variants and their use in anthropological investigations Studies using direct DNA analysis are now abundant. In some of these studies nuclear DNA polymorphisms were analyzed in a large number of loci and in others particular genetic materials such as those of maternal (mtDNA) or paternal (Y chromosome). However, in the first genetic investigations of human populations authors have used classical genetic markers such as those of ABO blood groups, the PI system of alpha 1 antitrypsin, HLA Loci, Rhesus system and particularly those of immunoglobulin GM system known by its unparalleled ability, of a single system, to differentiate human populations (for review see Chaabani, 2002). The frequency of different AAT alleles was widely used to characterize populations. The results obtained from studies, investigating the isoelectrofocusing technique (IEF) to discriminate between AAT variants, showed different allelic distribution among populations. These results, some of which are recapitulated in Table 1, show that sub-Saharan African populations were characterized by a relatively high frequency of PIM1 allele, which is less high in the European populations, and low presence of PIS and PIZ alleles. Furthermore, the molecular analysis of the two IEF- indistinguishable alleles PIM1Ala and PIM1Val showed that the ancestral PIM1Ala variant is more present in sub-Saharan subjects than in Europeans (Gaillard et al, 1994; Hayes, 2003). The Indian populations of South America were characterized by the high presence of PIM3 allele. On the other hand, PIM2, PIS and PIZ alleles were reduced. The European populations presented relatively high frequencies of the PIM2, PIS and PIZ alleles. This high presence of the PIM2 allele was also shared by the North African, Middle Eastern and Asian populations. On the contrary, PIS and PIZ alleles were rarely described in these populations. It is generally agreed that sub-Saharan Africans show more genetic diversity than Europeans and are therefore believed to be older (Jorde and Wooding, 2004) which confirms the high frequency of the ancestral PIM1Ala allele within the African population. The high presence of the PIM3 allele in the American Indian could be attributed to a genetic drift in this population likely originated from Central Asia immigrants around 40.000-16500 years ago (Spencer W and Mark R, 2002). However, an earlier immigration of these people before the PIM2 mutation occurrence